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GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)

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ClinicalTrials.gov Identifier: NCT04196413
Recruitment Status : Recruiting
First Posted : December 12, 2019
Last Update Posted : November 13, 2020
Sponsor:
Collaborator:
CureSearch
Information provided by (Responsible Party):
Crystal Mackall, MD, Stanford University

Tracking Information
First Submitted Date  ICMJE December 10, 2019
First Posted Date  ICMJE December 12, 2019
Last Update Posted Date November 13, 2020
Actual Study Start Date  ICMJE June 4, 2020
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2020)
  • Rate of successful manufacture of GD2CART using a retroviral vector in the Miltenyi CliniMACS Prodigy system [ Time Frame: 14 days after apheresis ]
    The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.
  • Maximum tolerated dose (MTD)/RP2D of GD2CART in subjects with H3K27M DIPG [ Time Frame: 28 days after infusion ]
    Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2CART cells, will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at each dose level tested in subjects with H3K27M-mutant DIPG following standard upfront radiation therapy.
  • Safety of GD2CART in subjects with spinal H3 K27M-mutant DMG treated at the RP2D [ Time Frame: 28 days after infusion ]
    Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2CART cells will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 in subjects with spinal H3K27M-mutant DMG following standard upfront radiation therapy
Original Primary Outcome Measures  ICMJE
 (submitted: December 10, 2019)
  • Rate of successful manufacture of GD2.BB.z.iCasp9-CAR T cells using a retroviral vector in the Miltenyi CliniMACS Prodigy system [ Time Frame: 14 days after apheris ]
    The percentage of apheresis samples (fresh or frozen) will be determined for each dose cohort.
  • Maximum tolerated dose (MTD)/RP2D of GD2.BB.z.iCasp9-CAR T cells with H3K27M DIPG or spinal H3 K27M-mutant DMG [ Time Frame: 28 days after infusion ]
    Severity of dose limiting toxicities (DLTs) following chemotherapy and infusion of GD2.BB.z.iCasp9-CAR T cells, will be recorded and graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 at each dose level tested in subjects with H3K27M-mutant DIPG and spinal H3K27M-mutant DMG following standard upfront radiation therapy.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2020)
  • Radiographic Response Rate [ Time Frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]
    Radiographic Response will be evaluated using tumor response criteria: Complete Response (CR): disappearance on MR of all evaluable tumor and mass effect; stable or improving neurologic examination. If CSF was positive, it must be negative. Partial Response (PR): ≥ to 50% reduction in tumor size; stable or improving neurologic examination. Stable Disease (SD): at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither PR nor PD Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression; OR a > 25% increase in the bi-dimensional measurement, OR the appearance of a new tumor lesion.
  • Overall Survival (OS) [ Time Frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]
    OS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of death from any cause
  • Progression-Free Survival (PFS) [ Time Frame: Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion ]
    PFS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of radiographic progression or death from any cause.
  • Post-progression survival (PPS) [ Time Frame: ime Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion ]
    PPS is measured for each subject with DIPG as OS minus PFS, and for each patient with recorded progression as OS minus Time to Progression (TTP)
  • Measure resolution of toxicity [ Time Frame: 72 hours of administration of AP1903 ]
    Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2CART cells within 72 hours
Original Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2019)
  • Overall Survival (OS) [ Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]
    OS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of death from any cause
  • Progression-Free Survival (PFS) [ Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]
    PFS is defined as the time from the start of the lymphodepleting chemotherapy preparative regimen to the date of radiographic progression or death from any cause.
  • Post-progression survival (PPS) [ Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]
    PPS is measured for each subject with DIPG as OS minus PFS, and for each patient with recorded progression as OS minus Time to Progression (TTP)
  • Radiographic Response Rate [ Time Frame: Day 28, 3 months, 6 months, 9 months and 12 months and 24 months post CAR T cell infusion. ]
    Radiographic Response will be evaluated using tumor response criteria:
    • Complete Response (CR): disappearance on MR of all evaluable tumor and mass effect; stable or improving neurologic examination. If CSF was positive, it must be negative.
    • Partial Response (PR): ≥ to 50% reduction in tumor size; stable or improving neurologic examination.
    • Stable Disease (SD): at least stable and maintenance corticosteroid dose not increased, and MR/CT imaging meets neither PR nor PD
    • Progressive Disease (PD): Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression; OR a > 25% increase in the bi-dimensional measurement, OR the appearance of a new tumor lesion.
  • Measure resolution of toxicity [ Time Frame: 72 hours of administration of AP1903 ]
    Resolution of toxicity ≤ grade2, in the event unacceptable toxicity considered possibly, probably or definitely related to GD2.BB.z.iCasp9-CAR T cells within 72 hours
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)
Official Title  ICMJE Phase 1 Clinical Trial of Autologous GD2 Chimeric Antigen Receptor (CAR) T Cells (GD2CART) for Diffuse Intrinsic Pontine Gliomas (DIPG) and Spinal Diffuse Midline Glioma (DMG)
Brief Summary The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.
Detailed Description

Primary Objectives:

  • Determine the feasibility of manufacturing autologous T cells transduced with 14g2a-CD8-BBz-iCasp9 retroviral vector expressing GD2 Chimeric Antigen Receptor (GD2CART) for administration in subjects with H3K27M+ diffuse intrinsic pontine glioma (DIPG) or subjects with spinal H3 K27M-mutant diffuse midline glioma (DMG) using a retroviral vector and dasatinib in the Miltenyi CliniMACS Prodigy® system.
  • Assess the safety and identify the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of GD2CART in subjects with H3K27M+ DIPG administered after cyclophosphamide/fludarabine-based lymphodepletion regimen using the following dose escalation schedule: DL1: 1e6 transduced T cells/kg; DL2: 3e6 transduced T cells/kg; DL3: 10e6 transduced T cells/kg.
  • Assess the safety of the MTD/RP2D of GD2CART in subjects with spinal H3K27M mutant DMG.

Secondary Objectives:

  • In a preliminary manner, assess clinical benefit of GD2CART at the RP2D in subjects with H3K27M DIPG or spinal H3 K27M-mutant DMG.
  • If unacceptable toxicity occurs that is possibly, probably or likely related to GD2CART, assess the capacity for AP1903, a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioma of Spinal Cord
  • Glioma of Brainstem
Intervention  ICMJE
  • Drug: GD2 CAR T cells
    Autologous T-Cells transduced with retroviral vector (14g2a-CD8.BB.z.iCasp9) expressing GD2-chimeric antigen receptor
  • Drug: Fludarabine
    Fludarabine 25 mg/m2 per day IV for days -4, -3, -2
  • Drug: Cyclophosphamide
    Cyclophosphamide 500 mg/m2 per day IV for days -4, -3, -2
Study Arms  ICMJE Experimental: GD2-CAR T

Dose escalation in subjects with DIPG:

A standard 3+3 dose escalation design will test GD2-CAR T cells in subjects with H3K27M-mutant DIPG, starting with Dose

Level 1:

  • Dose Level 1: 1x10^6 CAR+ T cells/kg body weight (+/- 20%)
  • Dose Level 2: 3x10^6 CAR+ T cells/kg body weight (+/- 20%)
  • Dose Level 3: 10x10^6 CAR+ T cells/kg body weight (+/- 20%)

Dose Level -1 will be explored if the first subject treated experiences dose limiting toxicity (DLT) or if >2 of 6 subjects treated at Dose Level 1 experiences DLT.

Dose expansion in subjects with DIPG and spinal DMG: Once the MTD or RP2D is determined, up to 20 evaluable subjects with H3K27M-mutant DIPG and 10 evaluable subjects with H3K27M-mutant spinal DMG will be treated at the RP2D (including subjects treated during dose escalation).

Interventions:
  • Drug: GD2 CAR T cells
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 10, 2019)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Disease Status:
  • Tissue diagnosis of H3K27M-mutated Diffuse Intrinsic Pontine Glioma (DIPG) with radiographically evident tumor restricted to the brainstem, OR
  • Tissue diagnosis of H3K27M-mutated Diffuse Midline Glioma (DMG) of the spinal cord
  • Age: Greater than or equal to 2 year of age and less than or equal to 30 years of age

Prior Therapy:

  • At least 6 weeks following completion of front line radiation therapy.
  • At least 3 weeks post chemotherapy or 5 half-lives, whichever is shorter must have elapsed since any prior systemic therapy, except for systemic inhibitory/stimulatory immune checkpoint therapy, which requires 5 half-lives.
  • Performance Status: Subjects > 16 years of age: Karnofsky ≥ 60% OR Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Subjects ≤ 16 years of age: Lansky scale ≥ 60%
  • Normal Organ and Marrow Function (supportive care is allowed per institutional standards, i.e. filgrastim, transfusion)

    1. Absolute neutrophil count (ANC) ≥ 1,000/uL
    2. Platelet count ≥ 100,000/uL
    3. Absolute lymphocyte count ≥ 150/uL
    4. Hemoglobin ≥ 8 g/dL
    5. Adequate renal, hepatic, pulmonary and cardiac function defined as:

      • Creatinine within institutional norms for age (i.e. ≤ 2 mg/dL in adults or according to table below in children <18 years) OR creatinine clearance (as estimated by Cockcroft Gault Equation) ≥ 60 mL/min
      • Age (Years) -- Maximum Serum Creatinine (mg/dL)
      • ≤5 Years ---------------- 0.8mg/dL
      • 5 < age ≤ 10 Years ----1.0mg/dL
      • >10-18 Years -----------1.2mg/dL
      • >18 Years -----------2.0mg/dL
      • Serum Alanine aminotransferase( ALT)/Aspartate Aminotransferase (AST) ≤ 3.0 Upper limit of normal (ULN )(grade 1)
      • Total bilirubin ≤ 1.5 mg/dl, except in subjects with Gilbert's syndrome.
      • Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant ECG findings
      • Baseline oxygen saturation > 92% on room air
  • Pregnancy Test Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization are not considered to be of childbearing potential).
  • Contraception Subjects of child bearing or child fathering potential must be willing to practice birth control from the time of enrollment on this study and for four (4) months after receiving the preparative lymphodepletion regimen or for as long as GD2-CAR T cells are detectable in peripheral blood or cerebrospinal fluid (CSF).
  • Ability to give informed consent. Pediatric subjects will be included in age appropriate discussion and verbal assent will be obtained for those > 7 years of age, when appropriate.

Exclusion Criteria:

  • Tumor involvement of cerebellar vermis or hemispheres (pontocerebellar peduncle involvement is allowed), thalamic lesions, or supratentorial lesions.
  • Clinically significant swallowing dysfunction.
  • Current systemic corticosteroid therapy
  • Prior CAR therapy.
  • Uncontrolled fungal, bacterial, viral, or other infection. Previously diagnosed infection for which the patient continues to receive antimicrobial therapy is permitted if responding to treatment and clinically stable.
  • Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti Hepatitis C Virus (HCV) positive). A history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative polymerase chan reaction (PCR) and/or nucleic acid testing.
  • Clinically significant systemic illness or medical condition (e.g. significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgement of the principal investigator is likely to interfere with assessment of safety or efficacy of the investigational regimen and its requirements.
  • In the investigator's judgment, the subject is unlikely to complete all protocol required study visits or procedures, including follow up visits, or comply with the study requirements for participation.
  • Known sensitivity or allergy to any agents/reagents used in this study.
  • Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 30 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Courtney Erickson 650-497-4276 gd2cart@stanfordchildrens.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04196413
Other Study ID Numbers  ICMJE IRB-52934
PEDSCCT6005 ( Other Identifier: OnCore )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Crystal Mackall, MD, Stanford University
Study Sponsor  ICMJE Crystal Mackall, MD
Collaborators  ICMJE CureSearch
Investigators  ICMJE
Principal Investigator: Michelle Monje Stanford University
PRS Account Stanford University
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP